The goal of this project is to develop procedures which will potentiate the activity of current and novel cancer chemotherapeutic agents. Binding, transport, cell membrane composition and agent detoxification are modified in an attempt to direct the active agent to susceptible tumor cells. Investigations are initiated in tissue culture and when applicable are extended to tumor bearing mice. Studies include (1) therapeutic interference with melphalan treatment by leucine and glutamine and its abolition by basic amino acids and by glutaminase:asparaginase, respectively and (2) differential competition for carrier-mediated transport of cytotoxic agents. In this approach, non-cytotoxic competitive substrates are used to discern the differences in structural requirements for transport between tumor cells and a sensitive host tissue such as the hematopoietic precursor cells of the white cell series. Knowledge of such differences is used both to develop bone marrow protective agents and to synthesize cytotoxic agents with greater specificity for the tumor cell.